Studies from our and other laboratories suggest that Interleukin 1 (IL-1) may be implicated in the pathogenesis of postmenopausal osteoporosis and that the antiresorptive effect of estrogen may be related to its ability to regulate the secretion of this cytokine from mononuclear cells. Since these cells secrete numerous cytokines (TNFalpha, GM-CSF, M-CSF, and IL-6) which all exerts multiple and overlapping effects on bone, the specific role of IL-1 in postmenopausal bone loss remains to be established. A possible experimental strategy to determine if IL-1 has a direct role in postmenopausal bone loss is to block its secretion or its effects on bone. This proposal describes studies to be carried out in oophorectomized rats aimed to investigate the effects on bone mass and bone turnover of a systemic and local treatment with IL-1 receptor antagonist (IL-1ra), a substance which blocks IL-1 binding to IL-1 receptors. To this aim, we will monitor the changes in 1) bone density, as estimated by x-ray bone densitometry in vivo and by direct physical and chemical measurements of bone specimens in vitro, and 2) histological and biochemical indices of bone turnover. Control treatments will be 17Beta estradiol and the IL-1ra suspension medium. The systemic effects of IL-1ra will be determined by infusing all substances in the subcutaneous tissue with an Alzet osmotic pump. The local effects of IL-1ra will be determined by infusing this agent directly into the femur trabecular bone of oophorectomized rats with a small catheter as described by Yamamoto and Rodan, using the other limb as a control. Additional aims of the proposed studies will be to determine whether the regulatory effect of estrogen on IL-1 secretion takes place at the transcriptional or the translational levels and whether this effect is confined to blood cells or is exerted on bone marrow cells as well. If the bone loss and the increase in bone turnover associated with oophorectomy are prevented by treatment with IL-1ra, the data will provide a strong evidence that IL-1 is directly involved, at least in rats, in the bone loss caused by estrogen withdrawal. The potential significance of this project is high and may a) provide a direct evidence of an involvement of IL-1 in the pathogenesis of postmenopausal bone loss, b) lay a foundation for an alternative form of preventive or therapeutic intervention in postmenopausal bone loss and c) lead to the characterization of the mechanism by which estrogen regulated IL-1 secretion in mononuclear cells.